The goal of the proposed research is to develop an effective pharmacological strategy to mitigate and treat radiation-induced skin injury in humans. Skin injury following a sub- lethal dose of ionizing radiation has important implications both for the treatment of malignant disease and for radiological protection. Significant injuries to the skin decrease the LD50/60 and amplify the risk for death at any radiation exposure dose. Available countermeasures are suboptimal especially with respect to acute and sub-acute phases of the skin injury. The proposal is based on the hypothesis that progressive damage to the skin after sub-lethal dose of radiation is in part due to reduced functioning of the tissue stem cells that can no longer replace differentiated functional cells, resulting in loss of homeostasis. We propose to replace the loss of radiation-sterilized stem cells with endogenous bone marrow derived endothelial and stromal (mesenchymal) stem cells. Specifically, we will determine the potential of the CXCR4 antagonist, plerixafor with vascular endothelial growth factor (VEGF) to mitigate radiation-induced skin injury. The rationale of the combined use of plerixafor and VEGF is to mobilize differentially subsets of progenitor cells from the bone marrow. Primary endpoints for evaluation will be functional using a semi-quantitative scoring system, skin strength and leg contraction in C57BL/6 mice. Secondary endpoints will include histopathology and pro-inflammatory cytokines (TGF-?, TNF-?). We recently obtained encouraging data showing that radiation skin injury could be significantly reduced by plerixafor, CXCR4 antagonist when the drug was applied days after the exposure. We expect that our proposed pharmacological approach has the potential to effectively restore tissue homeostasis after radiation. PUBLIC HEALTH RELEVANCE: The broad, long-term goal of the proposed research is to develop an effective mitigator for radiation-induced normal tissue and organ damage. If successful, our proposed strategy would be clinically more attractive than the existing approach;the endogenous bone marrow derived stem cells strategy should provide a safer approach than allogeneic and even allogeneic stem cell therapy.